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Crohn's Disease

Inflammatory bowel disease (IBD) is characterised by chronic intestinal inflammation. The two major types of IBD are Crohn's Disease (CD) and Ulcerative Colitis (UC), although other less common IBD conditions are also included in this category.

Introduction

Crohn's Disease causes inflammation of the bowel. It most commonly affects the lower small intestine (ileum) and the large intestine (colon), but may involve any part of the digestive tract from the mouth to the anus. The inflammation extends through the entire thickness of the bowel wall. Such inflammation can cause abdominal pain, diarrhoea and a range of other symptoms including fever and weight loss.

The disease occurs about equally in men and women and usually appears for the first time in patients ‹30 years old with peak incidence in those aged 14-24 years. A much smaller proportion of patients may develop Crohn's between the ages of 50 and 70 years but the disease can occur in people of any age. The cause of Crohn's Disease is unknown, although a family history of IBD has been associated with increased risk of an individual developing the disease. About 20% of people with Crohn's Disease have a blood relative with some form of IBD, most often a sibling and sometimes a parent or child. Cigarette smoking has also been shown to contribute to the development or exacerbation of Crohn's Disease.

Causes

The inflammation in Crohn's Disease has in the past been thought to be related to abnormalities in the body's immune system. The immune system is composed of cells and proteins that normally protect the body from infections and foreign bodies. In healthy individuals, there is usually no immune response directed against food, 'good' bacteria or other normal bowel components. In patients with Crohn's Disease however, the immune system seems to overreact to substances and bacteria in the intestine. White blood cells invade the intestinal lining and produce inflammatory toxins causing chronic tissue swelling, injury and ulceration. The precise cause of this abnormal immune response is unknown although the existence of a specific infectious agent has not been disproved. There also seems to be a genetic or inherited predisposition to develop Crohn's Disease. First-degree relatives (brother, sister, parent or child) of patients with Crohn's are more likely to develop the disease. Furthermore, certain chromosomal markers have been found in the DNA of patients with Crohn's Disease. Crohn's Disease is not caused by stress.

For years, scientists have been searching for an infectious cause of Crohn's Disease. A growing body of evidence suggests that a bacterium called Mycobacterium avium subspecies paratuberculosis (MAP) may infect a genetically susceptible subgroup of the population resulting in Crohn's Disease. Researchers here at the Centre for Digestive Diseases have been instrumental in revealing this possibility and remain at the frontline of international research into this area.

Symptoms

The most common symptoms associated with Crohn's Disease include abdominal pain, often in the right lower quadrant, and diarrhoea. Rectal bleeding, loss of appetite, fever and weight loss may also occur. Bleeding may persist and cause anaemia. Because Crohn's is a chronic disease, patients will experience periods of aggravation of symptoms and other periods of remission. During periods of active symptoms, patients may experience fatigue, joint pain and skin problems. Some patients may experience symptoms ranging from mild to severe. Children with Crohn's Disease may suffer delayed development and stunted growth.

People with Crohn's Disease may feel well and be free of symptoms for substantial spans of time when their disease is not active. Despite the need to take medication for long periods of time and occasional hospitalizations, most people with Crohn's Disease are able to hold jobs, raise families, and function successfully at home and in society.

Complications

Complications may develop as a consequence of the chronic inflammation in Crohn's Disease. These are usually only manifest in severe disease. The most common complication is blockage or obstruction of the intestine. Stiffening and narrowing of the bowel wall causes obstruction, which may result in constipation and poor absorption of nutrients leading to malnutrition. Some patients may develop tears in the lining of the anus (fissures). Inflammation may, in some cases, cause a fistula to form. This is a tunnel joining different loops of the bowel or connecting a portion of bowel to the bladder, vagina or the skin near the anus.

Nutritional complications are common in Crohn's Disease, including deficiencies of certain proteins, calories and vitamins. Other complications associated with Crohn's Disease include arthritis, skin problems, inflammation of the eyes and mouth, kidney or gall stones and liver disease. These problems often resolve with appropriate management for the inflammatory process, but sometimes require separate treatment.

Diagnosis

Crohn's Disease can be difficult to diagnose because its symptoms are similar to those of other GI disorders such as ulcerative colitis irritable bowel syndrome. To determine a diagnosis of Crohn's Disease, the Gastroenterologist must first obtain an accurate medical history from the patient, then perform a thorough physical examination and a series of other special investigations. Laboratory tests and x-rays are useful, often to exclude other forms of intestinal inflammation. Blood tests may be performed to check for anaemia, or high white blood cell count, which may indicate inflammation. Stools may be examined for occult bleeding or infection with a specific pathogen. The small intestine may be viewed with an upper GI x-ray after the patient swallows a chalky solution containing barium. The barium reveals areas of inflammation and other abnormalities in the bowel.

Colonoscopic procedures specifically aid diagnosis by allowing the doctor to visualise the bowel directly using a long flexible tube equipped with a miniature camera inserted into the anus. The doctor is able to see inflammation, ulceration or bleeding. Biopsies also may be taken. This involves the removal of a sample of intestinal tissue, for pathological testing to further confirm the extent and severity of inflammation. Cultures taken from aspirating luminal liquid will also be collected to look for secondary infection which may be causing the inflammation or aggravating it.

Treatment

Treatment for Crohn's Disease depends on the location and severity of disease, complications and response to previous treatment. The goals of current treatment strategies are to control inflammation, relieve symptoms and correct nutritional deficiencies. At this time, treatment can help control the disease, but there is no cure. Patients with Crohn's Disease may need medical care for a long time with regular doctor visits to monitor the condition.

Anti-inflammatory agents

The class of drugs known as aminosalicylates (5-ASA) are used to treat mild to moderate inflammation in Crohn's Disease. By controlling inflammation, these drugs are generally effective at inducing and maintaining remission of disease. They include sulphasalazine, mesalazine, olsalazine and balsalazide. Possible side effects of 5-ASA preparations include nausea, vomiting, heartburn, diarrhoea and headache. This type of drug has also been shown to have Anti-MAP activity and is usually combined with other drugs. Omega 3 fatty acids are also anti inflammatory agents which can be useful in therapy of IBD.

Immunosuppressive agents

Some patients take corticosteroids to control inflammation. These drugs non-specifically suppress the immune system and are used to treat moderate to severe Crohn's Disease. They treat the acute stages of disease by dramatically reducing fever and diarrhoea, relieving abdominal pain and tenderness, and improving appetite and general sense of well-being. They include prednisone in oral and rectal forms, IV. hydrocortisone and budesonide, oral or enema. Long-term corticosteroid therapy can induce serious side effects, most notably skin and bone changes and greater susceptibility to infection, and should be avoided if possible. Short term steroids can be very useful but long term steroids are now generally avoided.

Other immunosuppressive agents work by specifically blocking the immune reaction that contributes to the inflammation in Crohn's Disease. They work by specifically blocking immune reaction that contributes to inflammatory inflammation of Crohn’s Disease and most of them have anti-MAP activity. Azathioprine and 6-mercaptopurine improve overall clinical status, decrease the need for corticosteroids and help to maintain remission. Their action may not take effect for 2-6 months however and their use must be closely monitored for side effects such as nausea, vomiting, diarrhoea, allergy, decreased white blood cell count and pancreatitis. Other immunomodifiers such as methotrexate, cyclosporine and infliximab are sometimes used to treat severe Crohn's Disease that is non-responsive to other forms of treatment. Long term corticosteroids are avoided because they can cause more harm than good.

Antibiotic agents

Koch’s postulates have now been fulfilled proving that in a subset of patients the bacterium Mycobacterium Avium Paratuberculosis (MAP) is involved in the development and persistence of inflammation in Crohn’s Disease. Antimycobacterial agents specifically targeting this causative pathogen have shown success in inducing remission in severe disease and may even prove to be able to cure the disease in a subset of patients. The Centre for Digestive Diseases is a leader in this area of research and recently an Australia-wide trial has been completed against MAP, the results of which have shown that the highest reported remission can be achieved with anti-MAP therapy. Unfortunately, the trial used sub therapeutic doses, failed to test patients before they were treated for MAP presence and did not replace patients who were given non dissolving Clofazimine drugs so that the long term maintenance part of the trial cannot be currently accepted as having any clinical significance. Certain clinical trials have also shown that broad-spectrum antibiotics such as metronidazole and ciprofloxacin also have benefit in the treatment of Crohn’s Disease but need to be taken long term as they have known anti-MAP activity.

Surgery

Patients with Crohn's Disease may eventually require surgery. Surgery is used to solve specific problems such as stricture, obstruction, fistulae or overwhelming disease with non response. Cure is not achieved by surgery. The patient makes this decision after close consideration of information given by doctors, nurses, other patients and support groups.

Research

Crohn's Disease research has traditionally focussed on effective therapeutic relief of inflammatory symptoms. Recent efforts have shifted towards identifying specific infectious agents that may cause the disease. By targeting the particular causative agent with certain drugs, cure of Crohn's Disease is theoretically possible.

Anti-MAP. The bacterium, Mycobacterium avium paratuberculosis (MAP), is an infectious cause of Crohn’s Disease. Its causality has been proven by the standard Koch’s postulates which have been fulfilled by culturing the pathogen from patients with Crohn’s Disease, causing the disease to be reproduced in experimental animals, and then culturing back the bacterium from the experimental animals. Hence, a subset of patients with Crohn’s Disease – estimated to be around 50% - are suffering from this chronic inflammation caused by infection with MAP which is found in milk, water and foods generally. Prof John Hermon-Taylor of St George Hospital, London first used double therapy consisting of specific antibiotics Rifabutin and Clarithromycin, and obtained marked reduction inflammation in patients with Crohn’s. Clinically the symptoms in these patients with severe Crohn’s improved indicating that no anti-inflammatory activity is required to treat the condition. The dosing and composition of the therapy was improved by researchers led by Dr Thomas Borody at the Centre for Digestive Diseases and achieved remarkable and dramatic reversal of inflammation with healing in Crohn’s Disease together with long term remission of symptoms in inflammation in many patients. Interestingly, a subgroup of patients who were first diagnosed at the Centre for Digestive Diseases and had never been given anti-inflammatory agents still healed with antibiotics alone. As with all infective agents Mycobacterium avium paratuberculosis is not a single bacterium but has many subspecies and sensitivity profiles so that some of these bacteria respond much better than others as we see with Mycobacterium tuberculosis and with Helicobacter pylori. Other causes of Crohn’s like gut inflammation include Entamoeba histolytica and Mycobacterium tuberculosis and Mycobacterium bovis. Strongyloides stercoralis can produce a very similar picture and the Doctors at the Centre for Digestive Diseases examine patients for all of these known infections because treatment with specific anti-infective agents can potentially reverse the condition. Indeed Tuberculosis of the GI tract is quite indistinguishable from Crohn’s Disease and even sometimes looking for the bacteria with PCR has difficulty in locating the curable Tuberculosis agent as colonoscopy and histology can not distinguish the diseases (Ref – Entamoeba Histolytica: Another cause of Crohn’s Disease. T.J. Borody et al. Abstract ACG 2009)

Researchers continue to look for more effective treatments to dampen the inflammation stimulated by the infective agents. Other examples of investigational treatments include:

Anti-TNF. Research has shown that cells affected by Crohn's Disease contain an inflammatory protein produced by the immune system called tumour necrosis factor (TNF). This cytokine may be responsible for the inflammation in Crohn's Disease. Anti-TNF (eg. infliximab and adalimumab) binds to TNF and inactivates it before it can cause inflammation in the intestine. In studies anti-TNF seems particularly helpful in closing fistulae. Unfortunately it is plagued by numerous side effects and has a fairly poor track record in inducing remission with progressive loss of activity. Complications can be quite severe including overwhelming infection, demyelination of brain tissue, and development of various cancers. The restricted drug, thalidomide, also has anti-TNF properties and is being carefully investigated as a possible treatment for severe Crohn's Disease.

Budesonide- Also called entocortthis corticosteroid is not dramatically effective but has fewer side effects and is orally administered. Systemic corticosteroids such as Prednisone has certain advantages in its use. Methotrexate, Cyclosporine and Tacroimus- are immunosuppressive antibiotic medications that may be useful in severe Crohn's Disease and appear to work faster than traditional immunosuppressants. Please note that these are all anti-MAP agents and probably work more as antibiotics than immunosuppressants.

Nutritional supplementation

Nutritional supplements may be recommended, especially in children with impeded growth and development. Special high-calorie liquid formulas are sometimes used for this purpose. A small number of patients with absorption problems or malnutrition may require feeding by vein.